Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16(INK4a)

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16(INK4a) tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16(INK4a) and to the related p19(INK4d) reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Ttrmour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16(INK4a).
Publisher
MACMILLAN MAGAZINES LTD
Issue Date
1998-09
Language
ENG
Keywords

FAMILIAL MELANOMA; CRYSTAL-STRUCTURE; PROTEIN-KINASE; CELLULAR-TRANSFORMATION; RETINOBLASTOMA-PROTEIN; GENE-PRODUCT; TGF-BETA; P16; MUTATIONS; BINDING

Citation

NATURE, v.395, no.6699, pp.237 - 243

ISSN
0028-0836
URI
http://hdl.handle.net/10203/75220
Appears in Collection
CH-Journal Papers(저널논문)
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